The development of contrast agents for magnetic resonance imaging (MRI) in clinical settings continues to receive great attention (Merbach et al., The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging. John Wiley & Sons: New York, 2001). Paramagnetic metal chelates, such as Gd(III)-diethylenetriaminepentaacetic acid (Gd(III)-DTPA) (Magnevist), Gd(III)-N,N′,N′,N″,N′″-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane (Gd(III)-DOTA), and their analogs have proven to increase the relaxation rate of surrounding protons and have been widely used as MRI contrast agents (Lauffer, Chem. Rev., 1987, 87, 901-927 and Caravan et al., Chem. Rev., 1999, 99, 2293-2352). However, these low molecular weight agents have disadvantages such as rapid circulation and clearance rates in vivo, and relatively low molar relaxivity properties thus limiting time-dependent imaging studies or acquisition of highly resolved images of patients (Kobayashi et al., Adv. Drug Deliv. Rev., 2005, 2271-2286; Comblin et al., Coord. Chem. Rev., 1999, 186, 451-470; and Raymond et al., Bioconjugate Chem., 2005, 16, 3-8).
Attempts have been made to develop bifunctional chelates asimaging agents. Such attempts have led to the establishment of a library such as 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriamine pentaacetic acid (1B4M-DTPA), N-[2-amino-3-(4-isothiocyanatobenzyl)propyl]-cis-cyclohexyl-1,2-diamine-N,N′,N′,N″,N″-pentaacetic acid (CHX-A-DTPA), and 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (p-SCN-Bz-DOTA), that are potentially useful for forming Gd(III) complexes and thus MRI contrast agents (Brechbiel et al., Bioconjug. Chem., 1991, 2, 187-194 and Wu et al., Bioorg. Med. Chem. Lett., 1997, 5, 1925-1934). The bifunctional chelators permit, on the one hand, conjugation to biomolecules such as, antibodies and peptides, dendrimers, and other macromolecular structures (Milenic et al., Nature Reviews Drug Discovery, 2004, 3, 488-499), and chelation to metal ions, on the other hand.

The synthetic methods attempted in the past to prepare macromolecular conjugated bifunctional chelators have one or more drawbacks such as the use of large excess of reagents or the need to carry out extensive purification from impurities formed in the conjugation reaction.
Thus, there is a desire for an improved synthesis of macromolecular-based magnetic resonance agents.